Novel clonidine formulation

ABSTRACT

An oral clonidine dosage unit providing a twenty-four hour extended release profile following a single dose administration is provided. The dosage unit comprises a pharmaceutically effective amount of a coated complex comprising clonidine bound to a cationic exchange resin, which is characterized by a twenty-four hour release profile with a single peak, wherein said oral clonidine dosage unit provides a therapeutically effective plasma concentration for at least about 70%, or at least 85% of the twenty-four hour period following the single dose administration. Both liquid and solid formulations are provided, as are methods of treating a patient by a single administration of a formulation of the invention so as to achieve a therapeutic effect for 24-hours.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/009,27 filed Nov. 26, 2013, which is a continuation of U.S. patentapplication Ser. No. 12/908,796, filed Oct. 20, 2010, now U.S. Pat. No.8,623,409, all of which are hereby incorporated by reference in theirentireties.

BACKGROUND OF THE INVENTION

This invention relates generally to formulations containing clonidine,and more specifically, to a formulation providing a twenty-four hourrelease profile in a single daily dosage unit.

Clonidine (known chemically asN-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine) is characterizedby the structure:

The pharmaceutical product containing the hydrochloride salt ofclonidine is commercially available as Catapres® (USP from BoehringerIngelheim Pharmaceuticals, clonidine hydrochloride or2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride, MW 266.56).Catapres® is a centrally acting alpha-agonist hypotensive agentavailable in tablet form for oral administration in three dosagestrengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to0.087 mg of the free base. Another commercial tablet is available fromDixarit. The active drug is also available as a transdermal patch(Catapres-TTS), or as an injectable form to be given epidurally,directly to the central nervous system. This drug is useful for treatinga number of conditions and may also be used to ease withdrawal symptomsassociated with the long-term use of narcotics, alcohol and nicotine(smoking).

Some of the side effects described for clonidine, includinglightheadedness, dry mouth, dizziness, or constipation, are believed tobe associated with the timing of peak plasma concentrations afforded bythe current immediate release formulations. For example, currentimmediate release clonidine products are administered twice a day,providing two peak plasma concentrations 3-5 hours after eachadministration. This results in unwanted sedating effects during the daytime. When administered orally, dry mouth is also associated with peakplasma concentrations.

An extended release clonidine formulation has been described in U.S.Pat. No. 5,133,974. This document describes formulations comprising amixture of 0 to about 50% of an immediate release particle comprising acore of at least one drug and up to 100% of an extended release particlewhich comprises the immediate release particle additionally coated witha dissolution modifying system and optionally an additional drug. USPatent Publication No. 2008/0152709 (Jun. 26, 2009) describes a methodfor treating a patient with clonidine once daily in a dose of about 0.1to about 2 mg (based on the weight of the HCl salt form). Thecomposition is described as having a 24-hour profile of plasma clonidineconcentration that does not substantially fall below about 0.2 ng/mL anddoes not substantially exceed about 1 ng/mL. One dosage unit isdescribed as having (a) zero to about 50% by weight of particules of afirst kind comprising clonidine and having an immediate release profileand (b) about 50% to about 100% by weight of particles of a second kindcomprising clonidine and exhibiting an extended release profile. In someembodiments, this dosage form is described as having a peak plasmaclonidine concentration of about 4 to about 16 hours afteradministration. However, the document fails to provide any detailedillustrations of how to formulate clonidine so as to achieve thedescribed release profile.

U.S. Pat. No. 6,030,642, reports that it provides an extended releaseclonidine formulation in the form of a capsule, which avoids the “peakand trough” side effects of traditional oral clonidine formulations. Theformulation is indicated to be a homogenous mixture of clonidine, one ormore cellulose ethers, and one or more inert, pharmaceutically acceptedfillers.

The binding of drugs on ion exchange particles to achieve sustainedrelease has been described. Clonidine has been described as one drugwhich could be bound to such an ion exchange resin particle. See, e.g.,U.S. Pat. No. 5,296,228; U.S. Pat. Nos. 5,275,820; 4,996,047. Liquidsuspensions containing coated drug-ion exchange resin complexes andmatrices are described in US Published Patent Application No.US-2007-021511-A1 (Sep. 20, 2007).

There remains a need for methods for treating diseases or disordersusing clonidine in a way which minimizes the side effects associatedwith “peak” and “trough” effects, and which provides a more efficientway of dosing. There is also a need for orally deliverablepharmaceutical compositions useful in these methods.

SUMMARY OF THE INVENTION

The present invention provides a formulation of clonidine which providesa 24-hour profile in a dosage unit which is administered once daily.Advantageously, the dosage unit may be administered prior to bedtime, sothat the side effects associated with peak plasma concentrationfollowing current oral formulations occurs during the sleeping hours.

In one aspect, the invention provides an oral clonidine dosage unithaving a twenty-four hour extended release profile following a singleoral administration. The dosage unit comprises a pharmaceuticallyeffective amount of a coated complex comprising clonidine bound to acationic exchange resin, which provides having a twenty-four hourrelease profile with a single plasma concentration peak. This oralclonidine dosage unit provides a therapeutically effective plasmaconcentration for at least about 70%, or at least about 85% of thetwenty-four hour period following the single oral dose. In oneembodiment, the dosage unit is a solid, e.g., a tablet. In anotherembodiment, the dosage unit is a liquid suspension.

In another aspect, the invention provides an oral clonidinepharmaceutical composition comprising a once-a-day modified releaseformulation comprising a pharmaceutically effective amount of a barriercoated complex comprising clonidine bound to a cationic exchange resinwhich provides a mean plasma concentration in human patients of about0.49 (±0.09) ng/mL at about 7.8 hours (±1.7 hours) following a singleclonidine dose equivalent to about 0.2 mg clonidine hydrochloride.

In yet another aspect, the invention provides an oral clonidine dosageunit providing a twenty-four hour extended release profile following asingle oral dose, said dosage unit comprising a pharmaceuticallyacceptable amount of a coated complex comprising clonidine bound to acationic exchange resin comprising a sulfonated copolymer of styrenewith divinylbenzene in a ratio of about 1:120 to about 1:180 (optionallyin a matrix), and wherein the complex has a cured water-permeable, hightensile strength, water insoluble, barrier coating comprising anon-ionic polymer and a plasticizer and having an elongation factor inthe range of about 150% to about 400%. In one embodiment, the dosageunit comprises a multiplicity of coated clonidine-cation exchange resincomplexes, said coated complexes having an average particle size in therange of about 20 microns to about 200 microns.

In still a further aspect, the invention provides a method fordelivering an effective amount of clonidine for twenty-four hours in asingle oral dose. The method involves administering to a subject asingle oral clonidine dosage unit as described herein.

In yet another aspect, the invention provides a method for thepreparation of an oral once-daily clonidine delivery system without foodeffect, comprising the steps of coating a cationic exchange resin with acured water-permeable, high tensile strength, water insoluble, barriercoating comprising polyvinylacetate, and a plasticizer, said barriercoating having an elongation factor in the range of about 150% to 400%;and mixing clonidine hydrochloride and the cation exchange resin in aweight ratio of about 1:120 to about 1:180 under conditions which permitthe clonidine to form a complex with the cation exchange resin.

These and other advantages of the present invention will be readilyapparent from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a graph illustrating the mean clonidineconcentration-time profiles after administration of a clonidineformulation of the invention in tablet form under fasting condition (

) and profile of a clonidine formulation of the invention in tablet form(open triangle

) under fed condition or presence of food. A single dose of the testtablet formulation which contains 0.2 mg (clonidine HCl equivalent, 0.17clonidine free base) was administered. A single peak is obtained for thetest tablet formulation of the invention, independent of presence offood. The blood plasma profile of the test tablet formulation of theinvention demonstrates that the formulation of the invention providestwenty-four hour blood plasma levels.

FIG. 2 provides a graph illustrating the mean clonidineconcentration-time profiles after administration of a clonidine liquidsuspension formulation of the invention under fasting condition (

) and the profile of a clonidine liquid suspension formulation of theinvention (open triangle

under fed condition or presence of food. A single dose of the testliquid suspension formulation which contains 0.2 mg clonidine (clonidineHCl equivalent, 0.17 clonidine free base) was administered. A singlepeak is obtained for the test liquid suspension formulation of theinvention, independent of presence of food. The blood plasma profile ofthe test suspension formulation of the invention demonstrates that theformulation of the invention provides twenty-four hour blood plasmalevels.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a clonidine formulation which delivers a24-hour release effective plasma profile which exhibits no food effect.Due to the prolongation of the drug release of up to about 24 hours,compositions of the present invention are useful because the once-a-daydose provides a more consistent supply (release) of the clonidine topatients who otherwise may have to be take multiple doses a day, therebyexposing those patients to multiple peaks of the drug and unwanted sideeffects associated with such multiple peaks. In one embodiment, theinvention provides a multi-particulate homogeneous suspension system.This is especially beneficial in the case of small children, elderlypeople, or others, who have difficulty swallowing larger solid dosageforms such as tablets or capsules. In another embodiment, the inventionprovides a tablet formulation.

As used herein, the term “modified release” refers to compositions whichare characterized by having at least one of the active components havinga release over a period of at least about 6 to about 8 hours, and up to24-hours. The term “modified release” may include, e.g., compositionswhich are extended release formulations, sustained release formulations,or delayed release formulations. The release profile may be assessedusing in vitro dissolution assays known to those of skill in the art[e.g., USP basket method or Paddle Method, or channel flow method]. Therelease profile can be assessed in vivo (e.g., for bioavailabilitydeterminations), using plasma concentrations to assess maximumconcentration (Cmax) and area under the curve (AUC). Such assays arewell known to those of skill in the art.

“C_(max)” is the maximum observed plasma concentration, calculated asthe mean of the individual maximum blood plasma concentrations.

The term “mean maximum plasma concentration” (mean C_(max)) is definedfor the purposes of the present invention as the maximum mean plasmaconcentration.

“Mean plasma concentration” is the arithmetic mean blood plasmaconcentration.

The term “t_(max)” is the time at which C_(max) is achieved.

The term “T_(max)” is the time at which the maximum blood plasmaconcentration is observed for each individual participating in thebioavailability study.

AUC_(last) is the mean area under the plasma concentration-time curvefrom time 0 to the last with quantifiable concentration. This may becalculated using the log-linear trapezoidal rule that means lineartrapezoidal rule up to Tmax, and log trapezoidal rule for the remainderof the curve.

The term “AUC₀-Tmax” is the mean area under the plasmaconcentration-time curve from time 0 to T_(max) and is used as anindicator of the rate of drug absorption, or metabolite formation. It iscalculated as the arithmetic mean of the area under the plasmaconcentration-time curve from time 0 to T_(max) calculated for eachindividual participating in the bioavailability study.

The term “AUC₀-∞” or “AUC_(inf)”is the mean area under the plasmaconcentration-time curve extrapolated to infinity. It is calculated asthe arithmetic mean of the area under the plasma concentration-timecurve from time 0 extrapolated to infinity, calculated for eachindividual participating in the bioavailability study.

The term “half-life” is the apparent terminal elimination half-life.

The term “HVD” is the half value duration, that is, the time duringwhich clonidine concentrations are above one half the C_(max). Thisparameter is an indicator of the shape of the plasma concentration timecurve.

The term “immediate release” is the release of an active ingredient froma pharmaceutical formulation where the rate of release of the activepharmaceutical ingredient from the pharmaceutical formulation is notretarded by means of a controlled release matrix or other such means andwhere the components of the pharmaceutical formulation are designed suchthat, upon ingestion, maximum exposure of said active pharmaceuticalingredient to body tissues occurs in the minimum period of time.

The term “initial administration” is defined for purposes of the presentinvention as the first single dose of a formulation containing an activeingredient administered to a patient or subject or the first doseadministered to a patient or subject after a suitable washout period.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusiveley.

As used herein the term “about” means a variability of 10% from thereference given, unless otherwise specified.

A clonidine formulation of the invention has a 24-hour release whichprovides a single plasma concentration peak, independent of food intake(e.g., could be administered under both fasted and fed conditions).Following a single administration of a formulation containing a coatedclonidine-cation exchange resin complex matrix as described herein, themean peak plasma concentration is reached between about 6 and about 9hours after dosing; and at least about 70%, or at least about 85% of the24-hour period for the plasma concentration is above about 200 pg/mL,and the mean maximum peak concentration does not exceed about 580 pg/mLover the 24-hour period. [200 pg/mL has been generally recognized as theminimum effective dose for clonidine use as an anti-hypertensive agent(see, e.g., US patent application 2008/0152709 “clonidine compositionand method of use”)].

In another embodiment, a formulation containing the multi-particulate,barrier coated, clonidine-ion exchange resin complex matrix releasesclonidine in vivo following a single dose administration such that theduration over which the plasma levels of clonidine is equal or greaterthan about 50% of the peak plasma concentration is at least about 30hours. In still another embodiment, a formulation as described hereinreleases clonidine in vivo following single dose administration suchthat the duration over which the plasma level of clonidine is equal toor greater than about 75% of the peak plasma concentration is about 6hours or greater, at least about 12 hours, or at least about 18 hours.

In another embodiment, an oral, once-a-day, modified release clonidinepharmaceutical composition is provided. The composition comprises apharmaceutically effective amount of a coated complex comprisingclonidine bound to a cationic exchange resin which provides a meanplasma concentration in human patients of about 0.4 to about 5.4 ng/mLat about 6.1 to about 9.5 hours following a single clonidine dose ofabout 0.2 mg. The composition may be either a liquid suspension or atablet. In one embodiment, the pharmaceutical composition provides aplasma half-life of about 13.7 hours±about 3 hours for clonidine.

Clonidine-Cation Exchange Resin Complexes and Matrixes

Clonidine, N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine, ischaracterized by the structure:

Clonidine hydrocholoride, is an imidazoline derivative and exists as amesomeric compound. The chemical name is2-(2,6-dichlorphenylamino)-2-imidazoline hydrochloride. The structuralformula is:

In order to prepare a composition of the invention, one or more salts orone or more prodrugs of clonidine, or in a combination of such forms isused for complexation with an ion exchange resin as described herein.Clonidine in the form of its hydrochloride salt is availablecommercially.

Cationic exchange resins are readily selected for use as describedherein. Cationic exchange resins vary in strength, i.e., in theirability to exchange cations. In one embodiment, a relatively strongcationic resin, e.g., Amberlite® IRP69, manufactured by Rohm and Haas;or Duolite® AP143, a chloride form sytrene-divinylbenzene polymeric(cholestyramine resin) is selected. Alternatively, one may select arelatively weak cationic exchange resin, e.g., Amberlite® IRP88 [Rohmand Haas], a weakly acidic potassium form cation exchange resin with 4%cross-linked methacrylate (100 to 500 mesh, equiv to about 150 micronsto about 27 microns, ASTM standard) or Amberlite® 64 (a methacrylic acidand divinylbenzene polymer hydrogen form polacrilex resin, Rohm andHaas, purchased with a particle size ranging from 100 to 400 mesh (equivto 35 microns to 150 microns, ASTM standard size), capacity ˜10 meq/g bydry weight). Further, either regularly or irregularly shaped particlesmay be used as cation exchange resins according to the presentinvention. Regularly shaped particles are those particles thatsubstantially conform to geometric shapes such as spherical, elliptical,cylindrical and the like, which are exemplified by Dowex® 50WX8 (The DowChemical Company). Irregularly shaped particles are all particles notconsidered to be regularly shaped, such as particles with amorphousshapes and particles with increased surface areas due to surfacechannels or distortions. Irregularly shaped ion-exchange resins of thistype are exemplified by Amberlite® IRP-69 (Rohm and Haas), the use ofwhich is illustrated in the examples below. This cation exchange resinis a sulfonated polymer composed of polystyrene cross-linked with about8% of divinylbenzene, with an ion-exchange capacity of about 4.5 to 5.5meq/g of dry resin (H⁺-form). Another cation exchange resin havingsimilar properties is Dowex® 50WX8 (H+ form, linear formula,C₁₀H₁₂.C₁₀H₁₀.C₈H₈)_(x), 200-400 mesh particle size, which is equivalentto about 75 microns to about 35 microns, ASTM standard). However,Amberlite® IRP-69 consists of irregularly shaped particles with a sizerange of about 100 to about 500 mesh (about 150 microns to about 27microns, ASTM standard), whereas the Dowex® 50WX8 is more regularlyshaped. Resins are generally purchased with a size ranging from about 25microns to about 400 microns. However, other sizes may be selected, orlarger sized particles may be milled to provide smaller particle sizes.

The selected ion exchange resins may be further treated by themanufacturer or the purchaser to maximize the safety for pharmaceuticaluse or for improved performance of the compositions. Impurities presentin the resins may be removed or neutralized by the use of commonchelating agents, anti-oxidants, preservatives such as disodium edetate,sodium bisulfate, and so on by incorporating them at any stage ofpreparation either before complexation or during complexation orthereafter. These impurities along with their chelating agent to whichthey have bound may be removed before further treatment of the ionexchange resin.

Binding of clonidine to the ion exchange resin can be accomplished usingmethods known in the art, e.g., in an aqueous slurry. Once formed, theclonidine-ion exchange resin complex is collected by filtration andwashed with appropriate solvents to remove any unbound drug orby-products. The complexes can be air-dried in trays, in a fluid beddryer, or other suitable dryer, at room temperature or at elevatedtemperature.

The amount of clonidine that can be loaded onto a resin will typicallyrange from about 0.5% to about 50% by weight of the clonidine-ionexchange resin particles, or about 0.75% to about 1% by weight of theclonidine-ion exchange resin particles. A skilled artisan with limitedexperimentation can determine the optimum loading for any drug resincomplex. In one embodiment, loading of about 10% to about 40% by weight,more desirably, about 15% to about 30% by weight, of the drug-ionexchange resin particles can be employed. Typical loadings of about 25%by weight of the drug-ion exchange resin particles can be advantageouslyemployed.

In one embodiment, the composition of the invention contains clonidinecomplexed to a sodium polystyrene sulfonate resin in at a ratio of about1 wt clonidine (based on the weight of the clonidine salt) to about 100wt resin to about 1 wt clonidine (based on the weight of the clonidinesalt) to about 300 wt resin. In another embodiment, the clonidine (basedon the weight of the salt) to resin ratio is about 1:120 to about 1:180.In yet a further embodiment, the clonidine to resin ratio is about1:150.

Granulating Agents and Matrix Forming Polymers

As used herein, the term “matrix forming polymer” or “matrix formingpolymeric material” refers to a polymer-based solution which forms amatrix with the clonidine-ion exchange resin complex. This termencompasses both those water-insoluble polymers/co-polymers whichfunction as release retardants as described herein, and hydrophilicpolymers/co-polymers which have described in the literature asimpregnating or solvating agents. Suitably, the matrix forming polymeris non-reactive polymer with clonidine. In one embodiment, an ionexchange resin matrix may include more than one matrix-forming polymersystem. For example, a clonidine-ion exchange resin complex matrix maycontain both a hydrophilic and a hydrophobic polymer which had beenapplied, e.g., to facilitate granulation or coating. Such a matrixforming polymer is added in an amount which increases the total weightof the uncoated clonidine-ion exchange resin complex about 3 wt % toabout 30 wt %. However, higher or lower amounts may be selected.

In one embodiment, a hydrophilic polymer such as polyvinylpyrrolidone[e.g., such as may be purchased commercially as Kollidon 30] is combinedwith the clonidine-ion exchange resin complex in order to facilitategranulation prior to coating. Other hydrophilic polymeric granulatingagents may include water-soluble polymeric materials which have beendescribed in the art as impregnating agents or solvating agents andwhich function in the present application as granulating agents. In oneembodiment, the granulating agent is a polyethylene glycol. Examples ofdesirable impregnating/solvating agents include those described in U.S.patent application Ser. No. 11/724,966, filed Mar. 15, 2007, Publishedas US 2007-0215511A, Sep. 20, 2007, and Meadows, US 2003-0099711, whichare incorporated herein by reference, or in U.S. Pat. No. 4,221,778 andpublished US Patent application Publication No. US 2003/009971 A1, thedisclosures of which are incorporated herein by reference. Specificexamples of other impregnating agents include propylene glycol,polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose,hydroxypropyl cellulose, and sorbitol.

Alternatively, a hydrophobic polymer or a water-insoluble combination ofpolymers may be selected, such as those which have been described. Suchpolymers include those which have been previously described as releaseretardants. As with the other matrix forming polymers, the hydrophobicpolymer does not form a separate layer on the clonidine-ion exchangeresin complex, but forms a matrix therewith. Examples of suitablerelease retardants include, for example, a polyvinyl acetate polymer ora mixture of polymers containing same (e.g., KOLLICOAT SR 30D),cellulose acetates, ethylcellulose polymers (e.g., AQUACOAT™ ECD-30 orSURELEASE™), acrylic based polymers or copolymers (e.g., represented bythe EUDRAGIT family of acrylic resins), cellulose phthalate, or anycombination of such water-insoluble polymers or polymer systems. Theseretardants when used may further prolong or alter the release of thedrug from the ion exchange resin complex/matrix and maximize attainingthe desired release profile. Further, use of a release retardant permitin some cases lowering the amount of coating thickness needed to attaina prolonged drug release of up to 24 hours. These retardants can be usedin either substantially pure form or as a commercial preparationobtained from a vendor. The preferred release retardant is a polyvinylacetate polymer as described herein or an acrylic polymer from theEUDRAGIT family. Examples of suitable acrylic polymers from the EUDRAGITfamily may include, e.g., a copolymer comprising ethyl acrylate andmethyl methacrylate (e.g., EUDRAGIT NE-30D), or EUDRAGIT RS, RL30D,RL100, or NE, which are largely pH-independent polymers; although lessdesirable, certain pH-dependent members polymers including, e.g.,members of the EUDRAGIT polymer family, e.g., the L, S, and E, polymersmay be selected.

The quantity of a matrix forming polymer typically adds from about 3% toabout 30% or more by weight to the total weight of the uncoatedclonidine-ion exchange resin complex. In one embodiment, a hydrophobicpolymer such as those described as a release retardant is used at thelow end of this range, e.g., about 3 to about 10%, or about 5 to about8%, in order to minimize the release retardant effect. In anotherembodiment, a hydrophilic polymer is used at the high end of this range,e.g., about 15 to about 30%. In another embodiment, the matrix formingpolymer, if used, is in the range from about 5% to about 20% and mostpreferably in the range of about 10% to about 15% by weight of theuncoated clonidine drug-ion exchange resin complex matrix particles.

These matrix forming polymers can be added after a substantial amount ofcomplex formation has taken place. In the more preferred embodiment, thematrix forming polymer is added after the formation of clonidine-ionexchange resin complex. Upon admixing, the clonidine-ion exchange resincomplex particles with the matrix polymer (clonidine-ion exchange resincomplex-matrix), the mixture is dried and milled appropriately. In somecases, the milling may be carried out before the complete drying of theclonidine-ion exchange resin complex-matrix and then again furtherdrying followed by milling to obtain the desired characteristics. In oneembodiment, the clonidine-ion exchange resin complex matrix is milled orpassed through a sieve to provide a particle size ranging from about 40microns to about 410 microns to enhance mouth feel (i.e., texture), orabout 50 microns to about 250 microns. These particles may be eitherregularly or irregularly shaped. This may be performed both prior to andafter application of the matrix forming polymer, if any. In someembodiments, the average particle size of the uncoated clonidine-ionexchange resin complex-optional matrix is milled to a size of about 100to about 200 microns. These particle sizes may be determined using sieveanalysis through sieve shaking having USP standard wire mesh sievesconforming to ASTM specifications.

Following complexation of clonidine and the ion exchange resin, withoptional application of matrix forming polymer, water is typicallyremoved from a wet clonidine-ion exchange resin complex or matrix inorder to facilitate application of the barrier coating.

Coating System

Suitably, the composition of the invention contains a barrier coatingapplied over the clonidine-ion exchange resin complex-optional matrix asan aqueous dispersion, dried, and milled or passed through a screen suchthat the barrier coated clonidine-ion exchange complex and optionalmatrix in the size range described herein, i.e., in the range of about50 to about 410 microns. Suitably, the barrier coat is a non-ionic,water-permeable, water-insoluble pH-independent polymer or blend ofpolymers which provides a modified release profile to the clonidine.

In one embodiment, the aqueous dispersion is a water insoluble polymercomprising a polyvinyl acetate polymer, or a blend of polymerscomprising a polyvinyl acetate polymer. In one embodiment, the barriercoating further contains a plasticizer, which can facilitate uniformcoating of the clonidine-ion exchange resin complex-optional matrix andenhances the tensile strength of the barrier coating layer.

One coating composition useful in the present invention is applied inthe form of an aqueous dispersion containing an polyvinyl acetate (PVA)polymer based aqueous coating dispersion and a plasticizer. The PVA isinsoluble in water at room temperature. The PVA may be used in eithersubstantially pure form or as a blend. Where the barrier coatingcomprises a PVA polymer, the PVA polymer is present in an amount ofabout 70% to about 90% w/w of the final barrier coating layer, at leastabout 75%, at least about 80%, about 85% w/w of the final barriercoating layer. Generally, a plasticizer is used in the percent range, ora mixture of plasticizers combine to total about 2 to about 50% byweight of the coating layer, more preferably about 2.5% to about 20% byweight of the coating layer on the coated clonidine-ion exchange resincomplex. Preferably a plasticizer is in a range of about 5% to about 10%by weight of the coating layer based on the coated complex provides themost desirable properties. Suitable plasticizers may be water solubleand water insoluble. Examples of suitable plasticizers include, e.g.,dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinylalcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributylcitrate, tributyl citrate, triacetin, and Soluphor® P (2-pyrrolidone),and mixtures thereof. Other plasticizers are described in patentapplication publication US 2003/0099711 A1, May 29, 2003, page 4 (0041)the disclosure of which is incorporated herein by reference.

A commercial polyvinylacetate blend contains primarily a polyvinylacetate polymer, a stabilizer, and minor amounts of a surfactant such assodium lauryl sulfate. Where the barrier coating comprises PVP as thestabilizer component, the final barrier coating layer generally containsabout 5 to about 10% w/w of polyvinyl pyrrolidone. In one desiredembodiment, the aqueous based barrier coating solution is KOLLICOAT SR30 D (BASF Corporation) and whose composition is about 27% PVA polymer,about 2.7% polyvinylpyrrolidone (PVP), about 0.3% sodium lauryl sulfate(solids content 30% w/w), mixed with a plasticizer. See, also, U.S. Pat.No. 6,066,334 and U.S. Pat. No. 6,026,277, which is incorporated byreference herein. The PVP and surfactant help stabilize the aqueousdispersion of the PVA. Generally, such stabilizing components arepresent in an amount totaling less than about 10% w/w, and preferablyless than about 5% w/w. Optionally, a selected surfactant is present inan amount of about 1% or less. In one embodiment, the surfactant is anon-ionic surfactant. Optionally, an ionic surfactant may be selected.

In a particularly desirable embodiment, the desired modified release isobtained when the coating layer formed by application of the aqueousdispersion containing the KOLLICOAT™ SR-30D—plasticizer is dried andcured. Preferably, the coating is cured for about 1 to about 24 hours.In alternate embodiments, the coating is cured for about 4 to about 16hours, and preferably about 5 hours at high temperature, e.g., about 50°C. to about 65° C., and preferably about 60° C. Thus, in one embodiment,the clonidine-ion exchange resin complex-optional matrix has a curedwater-permeable, high tensile strength, water insoluble, barrier coatingcomprising a non-ionic polymer and a plasticizer and having anelongation factor in the range of about 150% to 400%. In one embodiment,the barrier coating comprises a polyvinyl acetate polymer, a stabilizer,a surfactant and a plasticizer. In one embodiment, a barrier coatingcomprises about 2.5 to about 10% of plasticizer, about 70 to about 90%polyvinylacetate, about 5 to about 10% polyvinylpyrrolidone, and about0.1 to about 1% surfactant.

Optionally, another barrier coating may be selected. See, e.g., thebarrier coatings described in Kolter et al, U.S. Pat. No. 6,066,334 andU.S. Pat. No. 6,046,277 and Mehta et al, US Published Patent ApplicationNo. US 2007-0215511A, published Sep. 20, 2007, and its counterpartapplication, WO 2007/109104, which are incorporated herein by reference.See, also, e.g., Wen, U.S. Pat. Nos. 6,046,277 and 6,001,392; Meadows,US Published Patent Application No. 2003/009971 and related applicationWO 03/020242; Sovereign Pharmaceuticals, WO 2006/022996 and relatedapplications US Published Patent Application Nos. US2005/232986;US2005/232987; US2005/232993; US2005/266032.

Alternatively, other known aqueous or non-aqueous barrier coatings havebeen described in the literature and/or which are commercially availablecould be used for the coating process, but are less desirable for thereasons described in US Patent Publication No. US 2007-0215511A and inthe literature cited in the background therein. See, e.g., Bess, et al,U.S. Pat. No. 7,067,116; Goede et al, U.S. Pat. No. 6,667,058, Wen etal, U.S. Pat. No. 6,001,392, among others. Such coating materialsinclude ethylcellulose based extended release coatings, e.g., Aquacoat™ethylcellulose polymer extended release coating and Surelease®.Surelease® is available from Colorcon as an aqueous ethyl cellulosedispersion containing water (70.6% w/w), ethylcellulose (18.8% w/w),ammonium hydroxide (4.4% w/w), a medium chain triglyceride (4.0% w/w),and oleic acid (2.2% w/w).

In one embodiment, the barrier coating layer is about 10% to about 70%,by weight, of the uncoated clonidine-ion exchange resin complex-optionalmatrix. In another embodiment, the barrier coating layer is about 30% toabout 50% by weight of the uncoated clonidine-ion exchange resincomplex-optional matrix, about 40% by weight of the clonidine-ionexchange resin complex-optional matrix prior to coating.

In another embodiment, the coating may be a EUDRAGIT™ brand acrylatebased coating materials [including, e.g., a poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride) polymer system]. For example, Eudragit Eudragit™ RS 30D [apH-independent, 30% aqueous dispersion of poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1)],or Eudragit™ RL 30D [a 30% aqueous dispersion, pH independent polymer,poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethylmethacrylate chloride) 1:2:0.2)] may be selected as the barrier coating.Typically, talc is added to these coatings to address issues associatedwith tackiness during processing and these coatings are not cured.

Following coating, the coating is dried and is cured. The coating istypically cured for about 1 to about 24 hours. In alternate embodiments,the coating is cured for about 4 to about 16 hours, and preferably about5 hours at high temperature, e.g., about 50° C. to about 65° C., andpreferably about 60° C.

The formulations of the invention are designed to provide a once-a-dayadministrable, 24-hour effective dose, having a single peak in itsrelease profile. In one embodiment, a composition of the invention hasthe fasting pK profile of the test compound in FIG. 1. In still anotherembodiment, a composition has the fed pK profile of the test compound inFIG. 1. In other embodiments, a composition of the invention has afasting pK profile of the test compound in FIG. 2. In still otherembodiments, a composition of the invention has a fed pK profile of thetest compound in FIG. 2. In one embodiment, the present inventionprovides a oral single dosage unit, which provides an in vitrodissolution profile of about 30% at one hour; about 25% to about 55% at3 hours; about 40% to about 75% at 6 hours; and not less than 70% at 24hours, and having a therapeutically effective plasma concentration forat least about 70%, and preferably at least about of the twenty-fourhour period following the single oral dose.

In one embodiment, the invention provides an oral clonidinepharmaceutical composition comprising a once-a-day modified releaseformulation, which is not affected by food. The extended releaseclonidine composition comprises a pharmaceutically effective amount of acoated complex comprising clonidine bound to a cationic exchange resin(optionally in a matrix) which provides a mean plasma concentration inhuman patients of about 0.5 ng/mL at about 6 to about 10 hours followinga single clonidine dose of about 0.2 mg. The composition may be in theform of a liquid suspension or a tablet. In one embodiment, the plasmahalf-life of clonidine following a single dose of the composition of theinvention is about 10 to about 18 hours. In another embodiment, theextended release clonidine composition comprises a pharmaceuticallyeffective amount of a coated complex comprising clonidine bound to acationic exchange resin (optionally in a matrix) which provides a meanplasma concentration in human patients of about 0.49 (±0.09) ng/mL at7.8 hours (±1.7 hours) following a single clonidine dose of about 0.2mg. The composition may be in the form of a liquid suspension or atablet. In one embodiment, the plasma half-life of clonidine following asingle dose of the composition of the invention is 13.7 hours±3 hours.

Finished Dose Formulations

The clonidine-ion exchange resin complex-optional matrix of the presentinvention, can readily be formulated with pharmaceutically acceptableexcipients according to methods well known to those of skill in the art.In one embodiment, these formulations contain a substantially barriercoated clonidine-ion exchange resin complex of the invention, optionallywith a matrix.

The clonidine-ion exchange resin complex-optional matrix compositionthus prepared may be stored for future use or promptly formulated withconventional pharmaceutically acceptable carriers to prepare finishedingestible compositions for delivery orally, nasogastric tube, or viaother means. The compositions according to this invention may, forexample, take the form of liquid preparations such as suspensions, orsolid preparations such as capsules, tablets, caplets, sublinguals,powders, wafers, strips, gels, including liquigels, etc. In oneembodiment, a tablet of the invention is formulated as an orallydisintegrating or chewable tablet. Such orally dissolving tablets maydisintegrate in the mouth in less than about 60 seconds.

Additionally, the barrier coated clonidine-ion exchange resincomplex-optional matrix compositions may be formulated usingconventional pharmaceutically acceptable carriers or excipients and wellestablished techniques. Without being limited thereto, such conventionalcarriers or excipients include diluents, binders and adhesives (i.e.,cellulose derivatives and acrylic derivatives), lubricants (i.e.,magnesium or calcium stearate, or vegetable oils, polyethylene glycols,talc, sodium lauryl sulfate, polyoxy ethylene monostearate), thickeners,solubilizers, humectants, disintegrants, colorants, flavorings,stabilizing agents, sweeteners, and miscellaneous materials such asbuffers and adsorbents in order to prepare a particular pharmaceuticalcomposition. The stabilizing agents may include preservatives andanti-oxidants, amongst other components which will be readily apparentto one of ordinary skill in the art.

Suitable thickeners include, e.g., tragacanth; xanthan gum; bentonite;starch; acacia and lower alkyl ethers of cellulose (including thehydroxy and carboxy derivatives of the cellulose ethers). Examples ofcellulose include, e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methylcellulose, microcrystalline cellulose(MCC), and MCC with sodium carboxyl methyl cellulose. In one embodiment,tragacanth is used and incorporated in an amount of from about 0.1 toabout 1.0% weight per volume (w/v) of the composition, and morepreferably about 0.5% w/v of the composition. Xanthan gum is used in theamount of from about 0.025 to about 0.5% w/v and preferably about 0.25%w/v. The compositions may include a humectant composition to give theliquid greater viscosity and stability. Suitable humectants useful inthe finished formulations include glycerin, polyethylene glycol,propylene glycol and mixtures thereof.

The oral liquid compositions of the present invention may also compriseone or more surfactants in amounts of up to about 5.0% w/v andpreferably from about 0.02 to about 3.0% w/v of the total formulation.The surfactants useful in the preparation of the finished compositionsof the present invention are generally organic materials which aid inthe stabilization and dispersion of the ingredients in aqueous systemsfor a suitable homogenous composition. Preferably, the surfactants ofchoice are non-ionic surfactants such as poly(oxyethylene)(20) sorbitanmonooleate and sorbitan monooleate. These are commercially known asTWEENS and SPANS and are produced in a wide variety of structures andmolecular weights.

Whereas any one of a number of surfactants may be used, preferably acompound from the group comprising polysorbate copolymers(sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl)) is employed.This compound is also added functions to keep any flavors and sweetenershomogeneously dissolved and dispersed in solution.

Suitable polysorbates include polysorbate 20, polysorbate 40,polysorbate 80 and mixtures thereof. Most preferably, polysorbate 80 isemployed. The surfactant component will comprise from about 0.01 toabout 2.0% w/v of the total composition and preferably will compriseabout 0.1% w/v of the total weight of the composition.

A second emulsifer/surfactant useful in combination with polysorbatesmay be employed and is preferably a poloxamer such as Poloxamer 407.Poloxamer 407 has an HLB (hydrophilic/lipophilic balance) of about 22and is sold under the tradename Pluoronic-127 (BASF—NJ). The twosurfactants can be employed in substantially equivalent amounts. Forexample, the Poloxamer 407 and polysorbate 80 may each be employedtogether at levels of approximately from about 0.02 to about 4.0% w/v ofthe total weight of the formulation.

Aqueous suspensions may be obtained by dispersing the clonidine-ionexchange resin compositions in a suitable aqueous vehicle, optionallywith the addition of suitable viscosity enhancing agent(s) (e.g.,cellulose derivatives, xanthan gum, etc). Non-aqueous suspensions may beobtained by dispersing the foregoing compositions in a suitablenon-aqueous based vehicle, optionally with the addition of suitableviscosity enhancing agent(s) (e.g., hydrogenated edible fats, aluminumstate, etc.). Suitable non-aqueous vehicles include, for example, almondoil, arachis oil, soybean oil or soybean oil or fractionated vegetableoils such as fractionated coconut oil.

Useful preservatives include, but are not limited to, sodium benzoate,benzoic acid, potassium sorbate, salts of edetate (also known as saltsof ethylenediaminetetraacetic acid, or EDTA, such as disodium EDTA),parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, etc.),and sorbic acid. Amongst useful preservatives include chelating agentssome of which are listed above and other chelating agents, e.g.,nitrilotriacetic acid (NTA); ethylenediaminetetracetic acid (EDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DPTA), 1,2-Diaminopropanetetraaceticacid (1,2-PDTA); 1,3-Diaminopropanetetraacetic acid (1,3-PDTA);2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);ethylenediamine (EDAMINE);Trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CDTA);ethylenediamine-N,N′-diacetate (EDDA); phenazine methosulphate (PMS);2,6-Dichloro-indophenol (DCPIP); Bis(carboxymethyl)diaza-18-crown-6(CROWN); porphine; chlorophyll; dimercaprol (2,3-Dimercapto-1-propanol);citric acid; tartaric acid; fumaric acid; malic acid; and salts thereof.The preservatives listed above are exemplary, but each preservative mustbe evaluated in each formulation, to assure the compatibility andefficacy of the preservative. Methods for evaluating the efficacy ofpreservatives in pharmaceutical formulations are known to those skilledin the art. Preferred preservatives are the paraben preservativesinclude, methyl, ethyl, propyl, and butyl paraben. Methyl and propylparaben are most preferable. Preferably, both methyl and propyl parabenare present in the formulation in a ratio of methyl paraben to propylparaben of from about 2.5:1 to about 16:1, preferably 9:1.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist: Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, high fructose corn syrup, dextrose,sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrupsolids and sugar alcohols such as sorbitol, xylitol, mannitol andmixtures thereof;

In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular liquid formulation. This amountwill normally be 0.001 to about 90% by weight, per volume of the finalliquid composition, when using an easily extractable sweetener. Thewater-soluble sweeteners described above, are preferably used in amountsof about 5 to about 70% by weight per volume, and most preferably fromabout 10 to about 50% by weight per volume of the final liquidcomposition. In contrast, the artificial sweeteners [e.g., sucralose,acesulfame K, and dipeptide based sweeteners] are used in amounts ofabout 0.005 to about 5.0% and most preferably about 0.01 to about 2.5%by weight per volume of the final liquid composition. These amounts areordinarily necessary to achieve a desired level of sweetness independentfrom the flavor level achieved from flavor oils.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, essential oils (i.e. thymol,eculyptol, menthol and methyl salicylate) and the like are contemplated.The amount of flavoring employed is normally a matter of preferencesubject to such factors as flavor type, individual flavor, and strengthdesired. Thus, the amount may be varied in order to obtain the resultdesired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. The flavorings are generally utilized in amounts thatwill vary depending upon the individual flavor, and may, for example,range in amounts of about 0.01 to about 3% by weight per volume of thefinal composition weight.

The colorants useful in the present invention, include the pigments suchas titanium dioxide, that may be incorporated in amounts of up to about1% by weight per volume, and preferably up to about 0.6% by weight pervolume. Also, the colorants may include dyes suitable for food, drug andcosmetic applications, and known as D&C and F.D. & C. dyes and the like.The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include indigoid dye,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5′indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1 comprises a triphenylmethane dye and is the monosodium saltof 4-[4-N-ethylp-sulfobenzylamino)diphenylmethylenel-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. and their correspondingchemical structures may be found in the Kirk-Othmer Encyclopedia ofChemical Technology, in Volume 5, at Pages 857-884, which text isaccordingly incorporated herein by reference.

Suitable oils and fats that are usable would include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients are generallyutilized in amounts with respect to the comestible product of up toabout 7.0% by weight, and preferably up to about 3.5% by weight of thefinal product.

Wetting agents also may be employed in the inventive compositions tofacilitate the dispersion of any hydrophobic ingredients. Theconcentration of wetting agents in the composition should be selected toachieve optimum dispersion of the ingredient within the composition withthe lowest feasible concentration of wetting agent. It should beappreciated that an excess concentration of wetting agent may cause thecomposition, as a suspension, to flocculate. Those skilled in the artare well versed in suitable empirical methods to determine theappropriate wetting agents and concentrations to achieve optimumdispersion and avoid flocculation. Suitable wetting agents are listed inthe US Pharmacopeia 32.

In another aspect, the invention provides a product containing a coatedclonidine-ion exchange resin complex-optional matrix of the invention.In some embodiments, the coated clonidine-ion exchange resincomplex-optional matrix of the invention are in packs in a form readyfor administration, e.g., a blister pack, a bottle, syringes, foilpacks, pouches, or other suitable container. In other embodiments, thecompositions of the invention are in concentrated form in packs,optionally with the diluent required to make a final solution foradministration. In still other embodiments, the product contains acompound useful in the invention in solid form and, optionally, aseparate container with a suitable suspension base or other carrier forthe drug-ion exchange resin complex useful in the invention. In stillother embodiments, the above packs/kits include other components, e.g.,a meter dose apparatus/device, instructions for dilution, mixing and/oradministration of the product, other containers, nasogastric tubes, etc.Other such pack/kit components will be readily apparent to one ofordinary skill in the art.

Methods and apparatus for delivery of drugs through nasogastric tubesare well known to those of ordinary skill in the art. See, e.g., E.Bryson, “Drug Administration via Nasogastric Tube”, Nurs Times, 2001,Apr. 19-25 97(16):51. The present invention can be readily deliveredusing such devices. Suitable nasogastric tubes are availablecommercially and/or have been described. See, e.g., U.S. Pat. No.5,334,166; U.S. Pat. No. 5,322,073; U.S. Pat. No. 4,619,673; U.S. Pat.No. 4,363,323.

Uses of Formulations

The formulations described herein are useful for delivering atwenty-four hour extended release profile of clonidine in a single oraldose. Suitably, the method involves administering to a subject a singleoral clonidine dosage unit as described herein. In one embodiment, thesingle oral clonidine dose is administered at night-time. Theformulations of the invention provide a therapeutically effective amountof clonidine for a twenty-four hour release profile which provides asingle peak plasma concentration, following a single administration ofthe oral clonidine dose.

Clonidine has been found useful in treatment of a wide range of diseasesand disorders, not all of which are known to be mediated bycatecholamines or even related to α-adrenergic activity. A list oftherapeutic uses of clonidine has been compiled, for example, by Faganet al. (2006) U.S. Pharmacist 5:HS2-HS16, which is incorporated byreference herein without admission that it constitutes prior art to thepresent invention. This and other publications describe diseases ordisorders for which clonidine is indicated as including, e.g.,circulatory disorders including hypertension and cardiovascular diseaserelated thereto, arrhythmia, myocardial ischemia, atrial fibrillation,congestive heart failure, allodynia, hyperalgesia, neuropathic pain,cancer pain, cluster headache, chronic headache, migraine, postoperativepain, spinal cord injury pain, akathisia, restless legs syndrome,peripheral neuropathy, neuralgia, orofacial pain, diabeticgastroparesis, chronic memory disorders, hypertonia, hyperkineticmovement disorders, Tourette's syndrome, substance withdrawal, attentiondeficit hyperactivity disorder, manic states, behavioral disordersrelated to encephalopathy, bipolar disorder, narcolepsy, post-traumaticstress disorder, schizophrenia, sleep disorders, social phobia,hyperthyroidism, growth delay, excessive sweating, hot flashes,trichorrhexis nodosa, and combinations thereof. Clonidine has also beendescribed as being useful to treat pain and/or inflammation in, e.g., USPublished Patent Application No. 2009/026449 A1 (Oct. 22, 2009), whichdescribes conditions including, e.g., pain due to a spinal discherniation (i.e., sciatica), spondilothesis, stenosis, osteoarthritis,carpal/tarsal tunnel syndrome, tendonitis, temporomandibular jointdisorder (TMJ) and discogenic back pain and joint pain, as well as painthat accompanies or follows surgery.

Optionally, a modified release formulation may contain one or moreimmediate release components. For example, the modified release, coatedclonidine-cation exchange resin-optional matrix particles describedherein may be formulated with an active component which may be inimmediate release form. By “immediate release”, it is meant for purposesof the present invention that the formulation containing thetherapeutically active agent(s) meets the disintegration and/ordissolution requirements for immediate release of the particulartherapeutically active agent(s), as set forth in the USP XXII, 1990 (TheUnited States Pharmacopeia). Generally, immediate release formulationsinvolve release of more than about 50% of the active agent in less thanabout 1 hour and greater than about 70% of the active agent in about 6hours.

Several formulations prepared according to the present invention havebeen prepared and release profiles assessed using a variant of the USPStandard Paddle tester. Twenty-four release profiles have been observedfor all of the formulations prepared by the working examples describedbelow.

The following examples illustrate the compositions of the inventions.These formulations are not limitations on the present invention.

EXAMPLES Example 1 Preparation of Clonidine Tablet Formulation: BarrierCoated Clonidine-Cation Exchange Resin Complex Matrix Modified ReleaseTablets, Equivalent to 0.2 mg Clonidine HCl A. Preparation of UncoatedClonidine-Cation Exchange Resin Complex Matrix

Ingredients Grams/batch Clonidine HCl 85 Sodium Polystyrene Sulfonate(Amberlite ™ 12750 IRP-69) Cation Exchange Resin Povidone (Kollidon ®30) 1134 Purified Water* qs* *Removed during processing

The clonidine-resin complex matrix was prepared by first adding 80 L ofpurified water into a vessel and dissolving clonidine HCl therein bycontinuous mixing. A sodium polystyrene sulfonate ion exchange resin(AMBERLITE™ IRP-69) was dispersed with continuous mixing to form aslurry and the mixing was continued for 60 minutes to permit formationof a clonidine-ion exchange resin complex. Water from the slurry wasremoved by filtration. The wet resin complex was rinsed twice usingpurified water and then dried until the moisture content was about 10%to about 20%. In a separate container, povidone (Kollidon® 30) wasdissolved into 2.834 kg of purified water (povidone solution). Thepovidone solution was then sprayed onto the wet resin complex withcontinuous mixing to form a uniform clonidine-resin complex matrix. Theresulting matrix granules were dried until the moisture content was inthe range of 10 to 20%. These semi-dried granules (clonidine-ionexchange resin complex matrix) were then milled using CO-MIL® brand millfitted with a 40 mesh screen. The granules were further dried to amoisture content of in the range of about 3% to about 7%. These driedgranules were passed through a 40 mesh screen using the CO-MIL® brandmill.

B. Coated Clonidine Cation Exchange Resin Complex Matrix

Ingredients Gms Uncoated Clonidine - Cation 3200 Exchange Resin Matrixof Part A Polyvinyl Acetate dispersion  4063** (Kollicoat ® SR 30D)**Triacetin USP  61 Purified Water* 2276 *Removed during processing,**contains 30% w/w solids

The coated clonidine-ion exchange resin complex matrix was prepared asfollows. The coating solution was prepared by mixing triacetin, purifiedwater and polyvinyl acetate dispersion (purchased commercially asKOLLICOAT® SR-30D, from BASF) in a container. The coating solution waspassed though a [ASTM standard] Sieve No. 40 mesh screen. The coatingprocess was performed in a VECTOR FLM-5™ fluid bed processor equippedwith a Wurster column by applying 6.4 kg of coating solution to 3.2 kgof the uncoated clonidine-cation exchange resin matrix prepared as inPart A, to afford the matrix with a 40% weight gain. The coatedclonidine-cation exchange resin complex matrix was then passed throughan ASTM standard sieve No. 40 mesh screen and placed in a hot air ovenat 60° C. for 5 hours. The cured, barrier coated complex matrix wasagain passed through No. 40 mesh screen (i.e., about 410 microns).

C. Clonidine 24-Hour Release Tablet, 0.2 mg Formula

kg/125,000 Ingredient mg/Tablet tablets I. Core Tablet CoatedClonidine - Cation Exchange 49.61 6.201 Resin Complex Matrix of Part BLactose Monohydrate 50.00 6.250 Microcrystalline Cellulose 188.39 23.549Crospovidone 9.00 1.125 Dental-Type silica 1.50 0.1875 MagnesiumStearate 1.50 0.1875 Total 300.00 37.500 II. Coated Tablet Opadry WhiteYS-1-18202-A 9.00 1.125 Purified Water** Qs Qs Total 309.00 38.625*Actual quantity may vary based on assay value, **Removed duringprocessing

Lactose monohydrate, crospovidone, coated Clonidine-cation exchangeresin matrix of Part B, dental-type silica, and microcrystallinecellulose were screened through #40 mesh screen and mixed using‘V’Blender for 10 minutes. Magnesium stearate was screened through #40mesh screen and added in a ‘V’Blender [5 cubic ft size, Patterson Kelly.Mixing continues for 5 minutes. The powder blend from ‘V’ blender wascompressed into tablets (equivalent to 0.2 mg clonidine HCl) at 3 to 10kp hardness using 0.5200″×0.2385″ capsule shape toolings (core tablets).A top coating solution was prepared by dispersing Opadry WhiteYS-1-18202-A in purified water. Coating process was performed inperforated coating pan by spraying coating solution on core tablets. Inan in vitro dissolution profile, the amount of clonidine released fromthe above-referenced dosage was observed to be not more than 30% at 1hour; about 25% to about 55% at 3 hours; about 40% to about 75% at 6hours; and not less than 70% at 24 hours.

Example 2 Barrier Coated Clonidine-Cation Exchange Resin Complex MatrixTablets, Equivalent to 0.3 mg Clonidine HCl A. Preparation of UncoatedClonidine-Cation Exchange Resin Complex Matrix

Ingredients gms/Batch Clonidine HCl 85 Sodium Polystyrene Sulfonate(Amberlite ™ 12750 IRP-69) Cation Exchange Resin Povidone (Kollidon ™30) 1134 Purified Water* Qs* *Removed during processing

The clonidine-cation exchange resin complex was prepared by adding 80 Lof purified water in to a vessel and then clonidine HCl, which wasdissolved by continuous mixing. Sodium polystyrene sulfonate (AMBERLITE™IRP-69) was dispersed in the vessel with continuous mixing to form aslurry and the mixing was continued for 60 minutes in order to permitformation of the clonidine-cation exchange resin complex. Water from theslurry was removed by filtration process. The wet clonidine-ion exchangeresin complex was rinsed twice using purified water. This wet resincomplex was then dried until the moisture content was about 10-20%. In aseparate container povidone (Kollidon™ 30) was dissolved in to 2.834 kgof purified water (povidone solution). The povidone solution was thensprayed on to the wet clonidine-cation exchange resin complex withcontinuous mixing to form a uniform matrix. The resulting clonidine-ionexchange resin complex matrix granules were dried until the moisturecontent was between 10-20%. The semi-dried granules were then milledusing CO-MIL™ brand mill fitted with a 40 mesh screen. The granules werefurther dried to a moisture content of around 3-7%. These driedclonidine-ion exchange resin complex matrix granules were again passedthrough a CO-MIL™ fitted with a 40 mesh screen.

B. Coated Clonidine-Cation Exchange Resin Complex Matrix

Ingredients gms/Batch Clonidine - Cation Exchange Resin 3200 Matrix (asprepared in Part A) Polyvinyl Acetate dispersion  4063** (Kollicoat SR30D)** Triacetin USP  61 Purified Water* 2276 *Removed duringprocessing, **contains 30% w/w solids

The coated clonidine-cation exchange resin complex matrix was preparedas follows. The coating solution was prepared by mixing triacetin,purified water and polyvinyl acetate dispersion (purchased from BASF asKOLLICOAT™ SR-30D) in a container. The coating solution was passedthough a Seive No. 40 mesh screen. The coating process was performed ina VECTOR FLM-5™ Fluid bed processor equipped with a wurster column byapplying 6.4 kg of coating solution to 3.2 kg of clonidine-cationexchange resin complex matrix prepared as described in Part A of thisexample, to provide a 40% weight gain. The coated clonidine-cationexchange resin complex matrix was then passed through a No. 40 meshscreen and placed in a hot air oven at 60° C. for 5 hours. The cured,barrier coated clonidine-cation exchange resin complex matrix was againpassed through No. 40 mesh screen.

C. Clonidine 24-Hour Tablet, 0.3 mg Formula

Kg/125,000 Ingredient mg/Tablet tablets I. Core Tablet CoatedClonidine - Cation 74.42 9.302 exchange resin complex matrix (preparedas described in part B) Lactose Monohydrate 75.00 9.375 MicrocrystallineCellulose 282.58 35.323 Crospovidone 13.50 1.688 Dental-Type silica 2.250.281 Magnesium Stearate 2.25 0.281 Total 450.00 56.250 II. CoatedTablet Opadry II Yellow 57U92682 13.50 1.688 Purified Water** Qs QsTotal 463.50 57.938 *Actual quantity may vary based on assay value,**Removed during processing

Lactose monohydrate, crospovidone, the coated clonidine-cation exchangeresin complex matrix prepared as described in part B of this example,dental-type silica and microcrystalline cellulose were screened through#40 mesh screen and mixed using ‘V’Blender [5 cubic ft size, PattersonKelly] for 10 minutes. Magnesium stearate was screened through #40 meshscreen and added in to ‘V’Blender, where mixing was continued for 5minutes. The powder blend from the ‘V’ blender was compressed intotablets (equivalent to 0.3 mg clonidine HCl) at 4 to 12 kp hardnessusing 0.5950″×0.2730″ capsule shape toolings (core tablets). A topcoating solution was prepared by dispersing Opadry II yellow 57U92682 inpurified water. The coating process was performed in perforated coatingpan by spraying coating solution on core tablets.

Example 3 Preparation of Barrier Coated Clonidine-Ion Exchange ResinComplex Matrix Liquid Suspension Formulation A. Preparation of UncoatedClonidine-Cation Exchange Resin Complex Matrix

Ingredients gms/Batch Clonidine HCl 85 Sodium Polystyrene Sulfonate(Amberlite ™ 12750 IRP-69) Cation Exchange Resin Povidone (Kollidon ™30) 1134 Purified Water* Qs* *Removed during processing

The clonidine-cation exchange resin complex was prepared by first addinginto a vessel 80 L of Purified Water and dissolving clonidine HCltherein by continuous mixing. A sodium polystyrene sulfonate cationexchange resin (AMBERLITE™ IRP-69) was dispersed with continuous mixingto form a slurry and the mixing was continued for 60 minutes in order topermit complexation of the clonidine and the cation exchange resin.Water from slurry was removed by filtration process. The wetclonidine-cation exchange resin complex was rinsed twice using purifiedwater. This wet resin complex was then dried until the moisture contentwas in the range of about 10 to about 20%. In a separate containerPovidone (Kollidon™ 30) was dissolved in 2.834 kg of Purified Water(Povidone solution). The Povidone solution was then sprayed on to thewet resin complex with continuous mixing to form a uniform matrix. Theresulting clonidine-ion exchange resin complex matrix granules weredried until the moisture content was in the range of about 10 to about20%. The semi-dried granules were then milled using CO-MIL™ fitted with40 mesh screen. The granules were further dried to a moisture content ofaround 3-7%. These dried clonidine-ion exchange resin complex matrixgranules were again passed through a CO-MIL™ mill fitted with a 40 meshscreen.

B. Coated Clonidine-Cation Exchange Resin Complex Matrix

Ingredients gms/Batch Uncoated Clonidine - Cation Exchange Resin 3200Complex Matrix (Prepared as in Part A) Polyvinyl Acetate dispersion 4063** (Kollicoat SR 30D)** Triacetin USP  61 Purified Water* 2276*Removed during processing, **contains 30% w/w solids

The coated clonidine-cation exchange resin matrix was prepared asfollows. The coating solution was prepared by mixing triacetin, purifiedwater and polyvinyl acetate dispersion (purchased from BASF asKOLLICOAT™ SR-30D) in a separate container. The coating solution waspassed though a Seive No. 40 mesh screen. The coating process wasperformed in a VECTOR FLM-5™ Fluid bed processor equipped with a Wurstercolumn by applying 6.4 kg of coating solution to 3.2 kg of the uncoatedclonidine-cation exchange resin complex matrix, that resulted in 40%weight gain. The coated clonidine-cation exchange resin complex matrixwas then passed through a Seive No. 40 mesh screen and placed in a hotair oven at 60° C. for 5 hours. The cured, barrier coatedclonidine-cation exchange resin complex matrix was passed through a 40mesh screen.

C. Preparation of Clonidine 24-Hour Release Suspension (Equivalent to0.1 mg Clonidine HCl per mL)

Ingredient Kg/Batch Purified Water 85.2 Citric Acid 0.379 Polysorbate 80K 0.208 High Fructose Corn Syrup 42 56.8 Sucrose 28.4 Starch InstantClearjel (anhydrous) 4.35 Glycerin 18.93 Propylparaben 0.038Methylparaben 0.34 Xanthan Gum (anhydrous) 0.38 Coated Clonidine -Cation 4.69 Exchange Resin Matrix of Part B Strawberry Banana flavor2.124 Purified Water Qs to 189.3 L

In order to prepare the coated clonidine-cation exchange resin matrixliquid suspension formulation, 85.2 kg of purified water was added intoa main process vessel. Citric acid, polysorbate 80, high fructose cornsyrup and sucrose were added and mixed until dissolved. Instant Clearjelwas slowly dispersed using high shear mixer. Glycerin was weighed in aseparate container and heated to 60-70° C. Propylparaben andmethylparaben were added into the heated glycerin (60-70° C.) and mixeduntil completely dissolved (Paraben Solution). Paraben Solution wascooled down to room temperature and xanthan gum was added (Gumdispersion). Gum dispersion was added into the main process vessel,while mixing with a high shear mixer. The coated clonidine-cationexchange resin matrix prepared according to part B of this Example wasadded slowly followed by strawberry Banana flavor was added. The finalsuspension was obtained by adjusting the volume to 189.3 L usingPurified water.

Example 4 In Vivo Plasma Profile A. Bioavailability Study of CoatedClonidine-Cation Exchange Resin Matrix Tablets

An open-label, randomized, three-period, three-treatment crossover,26-healthy adult subject study was conducted for the pharmacokineticstudy. Subjects received separate single-dose administration underfasted and fed conditions of 0.2 mg coated clonidine-cation exchangeresin matrix tablet prepared as described in Example 1. Subjects alsoreceived Catapres (1×0.1 mg) administered at 0 and 12 hours after fastedcondition. Blood samples were collected prior to and following each doseat selected times through 72 hours post-dose. The plasma samples wereanalyzed for Clonidine using a validated LC-MS-MS method. The meanconcentration-time profile is shown in FIG. 1.

For the 0.2 mg dose from a single oral dose of the tablet of Example 2under both fasted and fed conditions, the mean peak plasma concentrationunder both fasted and fed conditions is reached between 6-9 hours afterdosing; the mean 24-hour plasma concentration is above the 12-hourconcentration of the reference IR formulation (dosed twice at 0 and 12hour) under the same test condition; at least 85% of the 24-hour periodis above the trough concentration of the immediate release product(dosed twice at 0 and 12 hour) at 12 hour; at least 85% of the 24-hourperiod for the plasma concentration is above 200 pg/mL; the mean maximumpeak concentration does not exceed 580 pg/mL over the 24-hour period.

Cmax AUC_(last) AUC_(inf) Number of (pg/mL) (hr*pg/mL) (hr*pg/mL)subjects Clonidine Tablets, 0.2 575 ± 14090 ± 14560 ± 25 mg (Fastedcondition) 108 3186 3352 Clonidine Tablets, 0.2 539 ± 13160 ± 13560 ± 26mg (Fed condition) 105 3258 3389

B. Bioavailability Study of Coated Clonidine-Cation Exchange ResinMatrix Oral Suspension

An open-label, randomized, three-period, three-treatment crossover,26-healthy adult subject study was conducted for the pharmacokineticstudy. Subjects received under either fasted or fed conditions separatesingle-dose administration of the oral suspension containing the coatedclonidine-cation exchange resin matrix prepared as described in Example3, with the exception that that amount of the coated clonidine-cationexchange resin in Example 3C was doubled (to 9.38 kg/batch) in order toprepare a 0.2 mg/mL dosage form. Subjects also received Catapres (1×0.1mg) administered at 0 and 12 hours after fasted condition. Blood sampleswere collected prior to and following each dose at selected timesthrough 72 hours post-dose. The plasma samples were analyzed forClonidine using a validated LC-MS-MS method. The mean concentration-timeprofile is shown in FIG. 2.

For the 0.2 mg dose from a single oral dose of the liquid suspensionprepared as described above, under both fasted and fed conditions, themean peak plasma concentration under both fasted and fed conditions isreached in the range of 6 to 9 hours after dosing; the mean 24-hourplasma concentration is above the 12-hour concentration of the referenceIR formulation (dosed twice at 0 and 12 hour) under the same testcondition; at least 85% of the 24-hour period is above the troughconcentration of the immediate release product (dosed twice at 0 and 12hour) at 12 hour; at least 85% of the 24-hour period for the plasmaconcentration is above 200 pg/mL; the mean maximum peak concentrationdoes not exceed 580 pg/mL over the 24-hour period.

Cmax AUC_(last) AUC_(inf) Number of (pg/mL) (hr*pg/mL) (hr*pg/mL)subjects Clonidine suspension, 516 ± 13040 ± 13640 ± 24 0.2 mg (Fasted85.3 2378 2627 condition) Clonidine suspension, 488 ± 12830 ± 13370 ± 250.2 mg (Fed 89.4 3035 3393 condition)

Example 5 Preparation of Ethylcellulose-Coated Clonidine-Cation ExchangeResin Matrix A. Clonidine-Cation Exchange Resin Matrix

Ingredients gms/Batch Clonidine HCl 85 Sodium Polystyrene Sulfonate(Amberlite ® 12750 IRP-69) Cation Exchange Resin Povidone (Kollidon ®30) 1134 Purified Water* Qs* *Removed during processing

The clonidine-cation exchange resin matrix was prepared by first adding80 L of purified water in a vessel following which clonidine HCl wasadded and dissolved by continuous mixing. Sodium polystyrene sulfonateresin (AMBERLITE® IRP-69) was dispersed with continuous mixing to form aslurry and the mixing continued for 60 minutes to permit formation of acomplex between the clonidine and cation exchange resin. Water wasremoved from the slurry by filtration. Wet resin complex was rinsedtwice using purified water. Wet resin complex was dried until themoisture content is about 10-20%. In a separate container povidone(Kollidon® 30) was dissolved in 2.834 kg of purified water (Povidonesolution). The Povidone solution was then sprayed on to the wetclonidine-cation exchange resin complex with continuous mixing to form auniform matrix. The clonidine-cation exchange resin matrix granules weredried until the moisture content was between 10-20%. The semi-driedgranules were then passed through the CO-MIL™ fitted with a 40 meshscreen. The granules were further dried to a moisture content in therange of about 3% to about 7%. These dried granules were passed throughthe CO-MIL™ using a 40 mesh screen.

B. Ethylcellulose Coated Clonidine-Cation Exchange Resin Matrix

Ingredients gms/Batch Clonidine - Cation Exchange 1000  Resin Matrix ofPart A Aquacoat ™ ECD ** 1067** Dibutyl Sebacate NF 79 Purified Water*221  TOTAL 1400 

The coated clonidine-cation exchange resin matrix can be prepared asfollows. The coating solution is prepared by mixing ethylcelluloseaqueous dispersion (AQUACOAT™ ECD), dibutyl sebacate and purified waterin a separate container. The coating solution is passed though a SeiveNo. 40 mesh screen. The coating process is performed in a VECTOR FLM-1™fluid bed processor equipped with wurster column by applying 1369 g ofcoating solution to 1 kg of clonidine-cation exchange resin matrix,prepared according to Part A, to result in 40% weight gain. Theethylcellulose-coated clonidine-cation exchange resin matrix is thenpassed through a Seive No. 40 mesh screen and placed in the hot air ovenat 60° C. for 2 hours. The coated clonidine-cation exchange resin matrixis again passed through Sieve No. 40 mesh screen.

All patents, patent publications, and other publications listed in thisspecification are incorporated herein by reference in their entirety,including, but not limited to, U.S. patent application Ser. No.14/009,27 filed Nov. 26, 2013 and U.S. patent application Ser. No.12/908,796, filed Oct. 20, 2010. While the invention has been describedwith reference to a particularly preferred embodiment, it will beappreciated that modifications can be made without departing from thespirit of the invention. Such modifications are intended to fall withinthe scope of the appended claims.

What is claimed is:
 1. An oral clonidine composition having a singleplasma concentration peak following a single oral dose in a 24-hourperiod, said dosage unit comprising: pharmaceutically effective amountof cured, modified release barrier coated, clonidine-cation exchangeresin complex-matrix particles which comprise clonidine bound to acationic exchange resin in a ratio of about 1:120 to about 1:180clonidine to cation exchange resin in a particulate matrix with a matrixforming component, said matrix forming component comprising awater-insoluble polymer or copolymer or hydrophilic polymer orcopolymer, said cured barrier coating comprising polyvinylacetate and aplasticizer and being a cured, water-permeable, high tensile strength,water-insoluble, barrier coating having an elongation factor in therange of about 150% to 400%, wherein said cured barrier coating is overthe clonidine-cation exchange resin complex-matrix particles.
 2. Theoral clonidine composition according to claim 1, wherein theclonidine-cation exchange resin complex-matrix comprises a hydrophilicpolymer.
 3. The oral clonidine composition according to claim 1, whereinthe hydrophilic polymer is polyvinylpyrrolidone.
 4. The oral clonidinecomposition according to claim 1, wherein the matrix polymer is about 5%w/w to about 20% w/w added to the uncoated clonidine-cation exchangeresin complex.
 5. The oral composition according to claim 1, wherein thecured barrier coating comprises about 70% w/w to about 90% w/wpolyvinylacetate and about 2.5% w/w to about 10% w/w plasticizer.
 6. Amethod for delivering an effective amount of clonidine for a twenty-fourhour period which provides a single peak plasma concentration, themethod comprising administering to a subject a single oral clonidinecomposition according to claim 1 in the evening.